In Depression and Anxiety
In Schizophrenia
In Cardiovascular Disease
In Irritable Bowel Syndrome
In Delayed Gastric Emptying
In Pancreatic Exocrine Insufficiency
In Hormone Replacement

In Depression and Anxiety
Depression and anxiety are devastating and very common disorders that often occur together. 6% of the population suffers from depression, 2-3% from anxiety disorders. The onset of a depression or anxiety can occur at any time in a persons life. It affects people of all ages and in all episodes of life. Depression and anxiety have a severe impact on a persons ability to function in work, relationships and as parents.

The economic cost of this disease in the US alone is estimated at $53 billion annually. Although public information has much improved in the last decade, these disorder still have a considerable stigma attached to them. This makes it even harder for sufferers to deal with the disease.

Fortunately, these diseases are relatively treatable. 80-90% of sufferers can be treated with currently available antidepressants and anxiolytics. There is still room for improvement of therapy, though. Treatments with faster onset of action, fewer side effects, fewer chances of relapse after discontinuing treatment and no treatment resistance in anxiety treatments are needed.

Also, anxiety and depression are strongly related disorders. 50-70% of anxiety patients also suffer from depression, while 50% of depressed patients suffer from anxiety. One drug that could treat both sides of the coin would be an advantage to the patient.

The neurotransmitter serotonin plays an important role in the occurrence of depression and anxiety disorders. The Solvay Pharmaceuticals companies have housed one of the world’s major centers of serotonergic research for more than 20 years. This fundamental research at Solvay Pharmaceuticals has contributed substantially to the currently available body of knowledge on the involvement of serotonin in a wide variety of psychiatric disorders such as depression, anxiety, obsessive compulsive disorder and panic.

Solvay discovered LUVOX®, the world’s first selective serotonin reuptake inhibitor (SSRI). SSRI’s are now the most prescribed antidepressants in the world. LUVOX® is on the market for depression and obsessive compulsive disorder. Since the success of LUVOX®, Solvay has continued the search for even better therapies for this devastating disease. Serotonin continues to play an important role in this research. The knowledge on this neurotransmitter is combined with exploration of other mechanisms in order to find something that will bring a truly innovative medication.

Currently Solvay Pharmaceuticals has several compounds in the pipeline for depression and anxiety. One such compound is DU125530, a 5-HT1A antagonist for the treatment of major depression. 5-HT1A antagonists are able to increase serotonin levels in the brain, and are therefore expected to make good antidepressants. This compound is currently tested in small groups of patients (Phase-II trials).

Additionally, Solvay Pharmaceuticals has SLV308 in earlier stages for major depressive disorders as well as Parkinson’s disease and panic disorders. SLV308 is a compound with mixed effects on a number of different types of neurotransmitters, including noradrenaline, dopamine and 5-HT. The possible use of this compound in anxiety disorders, depression and Parkinson’s disease is relevant because these indications often overlap.
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In Schizophrenia
Schizophrenia is one of the most debilitating and elusive mental illnesses. It can occur at any age, including the very young. At any given time 1 to 2% of the population suffers from this disease. Schizophrenia is a disturbance in the thinking process, consisting of positive symptoms (symptoms that are ‘added’) and negative symptoms (abilities that are taken away). Positive symptoms are delusions, hallucinations, disorganized thinking and agitation. Negative symptoms are lack of drive or initiative, social withdrawal, apathy and emotional unresponsiveness.

Psychosis usually occurs in episodes. People suffering from schizophrenia may be perfectly healthy during long periods of time. During an acute episode they may however lose touch with the rest of the world completely. They may not know who they are, or who others are. Needless to say, schizophrenia is a very destructive disease that can be very difficult to cope with for sufferers as well as their relatives and friends. Schizophrenia is caused by a biological malfunctioning in the brain. Both dopamine and serotonin are found to play a role in the occurrence of schizophrenia.

With currently available therapies only positive symptoms are suppressed, negative symptoms remain. Also, there are serious side effects. Recently new drugs with a possibly improved profile have been introduced, but there is still much room for improvement of therapy.

Solvay is following several innovative approaches to improve existing dopamine therapy, combining dopamine and serotonin components. Also Solvay is researching targets in dopamine mechanisms. The dopamine plus serotonin-related targets have a somewhat higher chance of success than more innovative approaches. On the other hand, more innovative approaches may give a greater chance of eliminating disadvantages of current drug therapy. Therefore, we also focus on non-dopamine targets, such as neuropeptides and the cannabinoid receptor. These avenues, even though they have a higher risk of failure, have an even higher innovative value.

Research success has led to four drug candidates for psychosis in development so far. Furthest in development are the compounds DU127090, SLV310 and SLV313.
DU127090 is a mixed dopamine (D2) agonist / antagonist and also a
5-HT1A agonist, a unique profile with considerable innovative potential. It is currently being tested in small numbers of patients (Phase II clinical trials).
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Cardiovascular Disease
Cardiovascular disease is still the most common cause of illness and death, especially in the industrialized world. Urgently needed are new therapeutic concepts to prevent progression of disease and to provide better symptomatic improvement in advanced stages of this deadly disease. Solvay Pharmaceuticals’ cardiovascular research focuses on several different stages of cardiovascular disease.

Hypertension is one of the most important risk factors for cardiovascular disease. Solvay Pharmaceuticals has three antihypertensives on the market and continues the search for added value of different antihypertensive mechanisms. Although there are many antihypertensives available to sufferers, there is still room for improvement in therapy. At the moment, less than half of people with hypertension reach good blood pressure control with one single antihypertensive. Also, many people on antihypertensive therapy still struggle with side effects.

Research at Solvay Pharmaceuticals helped to shed new light on the role of metabolic abnormalities in the progression of cardiovascular disease. The product PHYSIOTENS® was a result of this research. Also, Solvay Pharmaceuticals is developing the new compound SLV 306, an antihypertensive with a dual effect, which may help more hypertensive patients to achieve adequate blood pressure control.

Congestive Heart Failure, the building up of fluid in the lungs and other parts of the body, when the heart is unable to pump effectively, is a severe condition. It is one of the most frequent causes of hospitalization of people over the age of 65. There is a high medical need for improvement of CHF symptoms such as congestion, vasoconstriction, increased pre- and afterload. Options to reduce these symptoms are to decrease fluid, salts retention and resistance of the blood vessels.

There is also a need for delay of disease progression, because, despite improvements by ACE inhibitor drugs, a lot of people still die from CHF.
The compound SLV 306 is one of Solvay Pharmaceuticals main research projects for congestive heart failure. SLV 306 at the same time blocks the formation of the vasoconstrictor (blood vessel tightening) endothelin and enhances the action of the vasodilating (blood vessel widening) natriuretic peptides. Therefore, SLV306 has a potentially powerful dual vasodilatory effect. Experts predict this kind of dual effect to hold promise for the future.

Atrial fibrillation is another important research target at Solvay Pharmaceuticals. Atrial fibrillation is the most commonly encountered form of arrhythmia (irregular heartbeat). Electrical signals in the heart are given very fast and uncontrolled, leading to a completely irregular heart beat. Atrial fibrillation occurs in 4% of the US adult population, according to the Framingham Heart Study (a 50 year examination of more than 7,000 volunteers in Framingham, Massachusetts).

When people get older, their chance of suffering from arrhythmia’s increases. Atrial fibrillation is an important cause of cardiovascular disease and death. It is estimated that the annual risk of stroke in patients with atrial fibrillation is as high as 4.5 percent. Atrial fibrillation is treated with different kind of therapies including medications. Treatments for atrial fibrillation have to be administered very carefully, in order not to induce a worsening of fibrillation. Risks and benefits have to be carefully weighed. The drugs nowadays available to treat atrial fibrillation are not well-tolerated. Also, some anti-arrhythmic agents have been associated with increased mortality due to their pro-arrhythmic effects.

For this high risk disease, Solvay Pharmaceuticals has tedisamil in advanced stages of development. Tedisamil (TEDANGIN®) ) improves the symptoms of angina by decreasing myocardial oxygen demand. At the same time, it improves the oxygen supply to the myocardium, the muscular substance of the heart. Tedisamil is a potassium channel blocker with specific bradycardic properties.
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In Irritable Bowel Syndrome
22% of gastrointestinal patients suffer from IBS. It is truly the common cold of gastrointestinal diseases. Unfortunately for many sufferers, it can be much more severe than a common cold. Irritable bowel syndrome causes pain, bloatedness, diarrhea and constipation. Ten to twenty percent of all adults experience symptoms of IBS. Only half visit a doctor for these symptoms. IBS is the second most common cause of work and school absenteeism, the first being the common cold.

The pain associated with irritable bowel syndrome can be so severe that sufferers cannot function properly. Present medication (like Solvay Pharmaceuticals DUSPATALIN® or DICETEL®) can successfully reduce abdominal pain, but there is a need for new approaches treating more of the IBS symptoms.

The expertise Solvay Pharmaceuticals has built up with their IBS products DUSPATAL® and DICETEL® have helped them identify new research targets for IBS. Solvay Pharmaceuticals has helped to elucidate the fact that IBS is not caused by structural, biochemical, or infectious abnormalities. Rather, IBS is considered to be an abnormality of brain-bowel function. In patients with IBS, there is found to be an increased pain sensitivity and abnormal muscular movement of the gut. Sometimes, the nerves are so sensitive that normal contractions, even when digesting a normal meal, bring on pain or discomfort. Serotonin and other neurotransmitters affect this sensitivity, and therefore Solvay Pharmaceutical is developing new compounds such as cilansetron that have an effect on these neurotransmitters.
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In Delayed Gastric Emptying
Delayed gastric emptying (Gastroparesis) is a condition in which the stomach empties food into the intestine too slowly. This can cause bloating, weight loss, nausea, and even vomiting. Gastroparesis occurs frequently in people with Diabetes Mellitus but can also occur in people without diabetes.

The symptoms, diet, and lifestyle restrictions that accompany delayed gastric emptying can seriously interfere with quality of life. Aside from the bothersome symptoms, complications may also occur. If food stays in the stomach for too long, it can cause problems, such as an overgrowth of bacteria due to fermentation. Also the food may harden and form so-called bezoars, that may cause nausea, vomiting, and obstruction in the stomach. Bezoars can be dangerous if they block the passage of food into the small intestine.

At least 20% of people with diabetes suffer from this condition, and for them it may be life threatening. An optimal blood glucose level is of primary importance for people with diabetes. This requires a careful balance of the correct amount of insulin, oral medications, food, exercise, etc. If the digestive system isn’t working properly, insulin levels become less dependable and this may lead to bouts of hypo- or hyperglycemia. The erratic digestion may also cause oral medications to lose their effect.

Satisfactory treatment for DGE is not available at this moment. Solvay is following several different approaches to Delayed Gastric Emptying. Previously, Solvay successfully developed PASPERTIN® (metoclopramide) for the treatment of DGE.

One of Solvay’s innovative approaches for the treatment of DGE is aimed at antagonizing CCK-A receptors, and has already led to a compound in development: tarazepide.

Another important avenue of research in DGE is motilin. Motilin is a hormone that is produced by the lining of the intestine. It stimulates contraction of the smooth muscles in the intestine, and plays an important role in the functioning of the digestive tract. Motilin agonists have been shown in clinical trials to speed up gastric emptying, and at the same time increase motility of the gastro-intestinal tract. Solvay’s motilin agonists SLV305 is currently in Phase I trials for the treatment of patients with gastro-intestinal disorders caused by reduced intestinal mobility. This includes DGE, but also gastro-esophageal reflux disease (GERD), IBS, and constipation.
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In Pancreatic Exocrine Insufficiency
Pancreatic exocrine insufficiency is part of a number of different conditions such as cystic fibrosis, chronic pancreatitis, and following pancreatic surgery. Solvay Pharmaceuticals’ CREON® product line is used to treat pancreatic exocrine insufficiency. Solvay Pharmaceuticals is the frontrunner in developing new and better formulations, maximizing the activity of the enzymes.

Recent studies have shown that diabetic patients often have pancreatic exocrine insufficiency, although they are not aware of it. It is not surprising, as the exocrine and endocrine functions are closely linked. Therefore it makes sense that patients with endocrine problems may have exocrine problems as well. This can manifest itself by maldigestion, and subsequent variations in blood glucose levels. People with diabetes may therefore be helped with an adequate amount of pancreatic exocrine enzymes. Solvay is currently investigating the usefulness of CREON® for pancreatic exocrine insufficiency in people with diabetes in Phase II clinical trials. [back to top]

In Hormone Replacement
The menopause is a relatively modern phenomenon; in past centuries most women died before they had a chance to reach it. Now women can expect to experience not only the menopause but also many years of potentially productive life afterwards.
About 80 per cent of menopausal women develop tiresome, unpleasant physical and psychological problems that are entirely or partly due to changes in their estrogen levels. Such symptoms can make their lives a misery.

Yet many women of this age could otherwise be enjoying themselves. As recent surveys show, many women report very positive feelings about this time in their lives; they feel more self-confident than in their youth, more tolerant and more philosophical. However, these same surveys also show, that climacteric symptoms often interfere with these feelings of well-being.

Solvay Pharmaceuticals has several hormone replacement therapies on the market worldwide, and is currently developing three new products for women’s wellbeing during and after the menopause.

Some women prefer skin applications to oral therapy for the treatment of natural hormone decline with aging. For them, Solvay Pharmaceuticals is developing several options in gel and patch form. ESTROGEL® is currently under FDA review as transdermal treatment for vasomotor symptoms of the menopause, such as hot flushes and night sweats. ESTROGEL® is administered once-daily, rapidly absorbed and doesn’t stain on clothing. The estradiol accumulates in the skin and forms a reservoir which gives off estradiol during the day in a steady dosage. ESTROGEL® was marketed by another company in Europe for many years, and is a popular estrogen, especially in France.

Currently in Phase III trials is a combination HRT Transdermal Patch for the relief of vasomotor symptoms of the menopause. This combination patch contains estradiol and levonorgestrel and is in development for the US market.
Additionally, Solvay Pharmaceuticals is developing the first combination HRT gel, called COMBIGEL®. So far, no other company has been able to develop a topical gel that contains both estradiol and a progestogen. To overcome the difficulties in delivering progestogen through the skin, Solvay Pharmaceuticals is using a patented permeation enhancer developed by the Swiss drug delivery company Permatec.

Males also appear to suffer from declining sex hormone production with aging. Hormone replacement therapies for this so-called “Andropause” are starting to appear, like ANDROGEL®. ANDROGEL® is the first topical testosterone product, launched in the US mid-2000 by Unimed, a subsidiary of Solvay Pharmaceuticals Inc.
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